Process for the preparation of lenalidomide

Abstract

The present invention relates to a process for the preparation of lenalidomide, wherein the process comprises: reducing 3-(4-nitro-loxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione to obtain lenalidomide.

1 . A process for the preparation of 3-(4-nitro-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione of Formula II, 
       
         
           
           
               
               
           
         
         wherein the process comprises reacting methyl 2-bromomethyl-3-nitrobenzoate of Formula III 
       
       
         
           
           
               
               
           
         
         with 3-aminopiperidine-2,6-dione or its salt in the presence of an organic solvent at a temperature of about 50° C. or below to obtain 3-(4-nitro-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione of Formula II. 
       
     
     
         2 . A process for the preparation of lenalidomide, wherein the process comprises,
 a) reacting methyl 2-bromomethyl-3-nitrobenzoate of Formula III   
       
         
           
           
               
               
           
         
         
           with 3-aminopiperidine-2,6-dione or its salt in the presence of an organic solvent at a temperature of about 50° C. or below to obtain 3-(4-nitro-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione of Formula II, and 
         
       
       
         
           
           
               
               
           
         
         b) reducing 3-(4-nitro-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione of Formula II to obtain lenalidomide. 
       
     
     
         3 . A process according to  claim 1  or  2 , wherein the methyl 2-bromomethyl-3-nitrobenzoate of Formula III is reacted with 3-aminopiperidine-2,6-dione or its salt at a temperature of about 20° C. about 45° C. 
     
     
         4 . A process according to  claim 1  or  2 , wherein the organic solvent comprises a water-miscible solvent. 
     
     
         5 . A process according to  claim 4 , wherein the organic solvent comprises N,N-dimethylformamide, dimethylformamide, C 1-4  alkanol, C 3-6  ketone or acetonitrile, or a mixture thereof. 
     
     
         6 . A process according to  claim 1  or  2 , wherein the 3-(4-nitro-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione of Formula II has a purity of about 99.0% or above. 
     
     
         7 . A process for the preparation of lenalidomide, wherein the process comprises:
 a) reducing the 3-(4-nitro-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione of Formula II in a solvent system comprising N,N-dimethylformamide   
       
         
           
           
               
               
           
         
         
           to obtain lenalidomide; and 
         
         b) isolating lenalidomide from the reaction mixture thereof. 
       
     
     
         8 . A process according to  claim 7 , wherein the N,N-dimethylformamide is used as a single solvent or in combination with one or more water-miscible organic solvents. 
     
     
         9 . A process according to  claim 8 , wherein the water-miscible organic solvent comprises methanol. 
     
     
         10 . A process according to  claim 7 , wherein the solvent comprises a volume, which is about 2 times to about 50 times more than the weight of 3-(4-nitro-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione of Formula II. 
     
     
         11 . A process according to  claim 7 , wherein the lenalidomide has a purity of greater than about 99.8%.